Allogeneic iPSC-Derived CAR-T Cells with Dual Antigen Targeting
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Solution Overview
Problem
Current CAR-T cell therapies for cancer are limited by high production costs, inefficient anti-tumor responses, particularly in solid tumors, limited penetration of CAR T cells into the tumor microenvironment, poor persistence of CAR-T cells, and adverse events such as cytokine release syndrome and graft-versus-host disease.
Innovation Solution
Genetically engineered induced pluripotent stem cells (iPSCs) and their derivative cells are developed to express a chimeric antigen receptor (CAR) targeting CD22 and optionally CD19, along with additional genetic modifications to enhance their therapeutic efficacy and safety, such as deletion of B2M and CIITA genes, expression of HLA-E and HLA-G, and inclusion of a safety switch.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autologous CAR-T cells are generated on a custom-made basis, then patient-specific anti-tumor activity is improved, but production costs and manufacturing time increase significantly
Solution Approach 1:
The patent uses allogeneic CAR-T cells as a 'copy' or substitute for autologous CAR-T cells. Instead of custom-making patient-specific cells, the invention employs off-the-shelf allogeneic cells that can be manufactured in advance and stored, eliminating the need for individualized production while providing comparable therapeutic effects
Solution Approach 2:
The patent implements preliminary action by pre-manufacturing and banking allogeneic CAR-T cells before patient treatment. The cells are generated, quality-tested, and stored in advance, allowing immediate administration to patients without waiting for custom production, thus improving both productivity and reliability
2Reliability
If CAR-T cells are used to treat solid tumors, then anti-tumor response is attempted, but penetration into tumor microenvironment and persistence in vivo are limited
Solution Approach 1:
The patent modifies key parameters of CAR-T cells including engineering them to secrete cytokines (IL-7, IL-15, IL-21) to alter the tumor microenvironment, modifying surface molecules to improve persistence, and adjusting CAR structure to enhance tumor penetration and sustained anti-tumor activity
3Reliability
If dual-antigen targeting CARs are used, then antigen downregulation resistance is improved, but manufacturing complexity increases
Solution Approach 1:
The patent merges multiple functions into a single CAR construct that targets both CD19 and CD22 antigens simultaneously. This bispecific CAR design allows the cell to recognize and attack tumor cells expressing either antigen, preventing escape through antigen downregulation while simplifying manufacturing compared to using separate CAR constructs
4Reliability
If CAR-T therapy is administered, then anti-tumor activity is enhanced, but adverse events such as cytokine release syndrome and graft-versus-host disease occur
Solution Approach 1:
The patent converts potentially harmful effects into beneficial outcomes by engineering CAR-T cells to secrete controlled amounts of cytokines (IL-7, IL-15, IL-21) that normally cause adverse reactions. These engineered cytokines enhance anti-tumor activity and cell persistence while being regulated to prevent severe adverse events like cytokine release syndrome
Solution Approach 2:
The patent introduces safety switches and regulatory mechanisms as intermediaries between the CAR-T cells and the patient's body. These include suicide genes, antigen-dependent activation requirements, and controlled cytokine secretion systems that mediate the interaction to prevent harmful adverse events while maintaining therapeutic efficacy
Data Source
AI summary
Provided are genetically engineered induced pluripotent stem cells (iPSCs) and derivative cells thereof expressing a chimeric antigen receptor (CAR) and methods of using the same. Also provided are compositions, polypeptides, vectors, and methods of manufacturing.